Head & Neck cancer (HNC) is the sixth most prevalent cancer worldwide, with over 600,000 new diagnoses annually. Epidermal growth factor receptor (EGFR) is overexpressed in HNC and leads to poor prognosis. Surprisingly, however, FDA-approved drugs that inhibit canonical EGFR signaling have had limited success in the clinic, suggesting that disease progression relies on non-canonical mechanisms of EGFR signaling. We have discovered such a non-canonical mechanism that consists of a hexameric receptor complex organized by syndecan-4 (Sdc4) containing EGFR, the hepatocyte growth factor receptor homologue MST1R/RON, the laminin-binding ?3?1 and ?6?4 integrins, and a second syndecan, Sdc2. RON and the cytoplasmic/nuclear kinase c-Abl become constitutively activated when incorporated into this complex, suppressing activation of p38MAPK that would otherwise cause immediate cessation of DNA synthesis and S-phase arrest. A peptide (SSTNEGFR) that represents the extracellular docking site in Sdc4 competitively blocks the formation and signaling of this receptor complex. Preliminary findings show that SSTNEGFR prevents the invasion of HNC cells and induces their rapid cell cycle arrest. Whereas invasion relies on active EGFR, cell cycle progression depends on EGFR but not its kinase activity, identifying a non-canonical EGFR signaling mechanism that is likely to be a critical new therapeutic target in cancers such as HNC that overexpress EGFR. Remarkably, SSTNEGFR does not cause cell cycle arrest in normal oral epithelial cells. Specifically, we plan to: (1) define the molecular organization and signaling mechanism of the Sdc:RTK:ITG complex, focusing on molecular interactions used by the two syndecans to assemble this complex, (2) identify the c-Abl and p38MAPK targets that govern stress signaling and S-phase arrest, and (3) test the efficacy of SSTNEGFR against human HNC patient-derived xenografts (PDXs) and the 4-NQO mouse model of HNC to determine at what stages in the initiation and progression HNC the therapeutic is effective. Our goal will be to understand the molecular underpinnings of this unique receptor complex, understand how it drives HNC and identify it as a possible new target for therapeutics to treat HN disease.